Kinase inhibitors are rapidly becoming one of the most validated and pursued class of drug targets. Janus kinases (JAKs) comprise a family of 4 kinases that play multiple roles downstream of cytokine signalling in both immune and non-immune cells. Autoimmunity is driven by an aberrant adaptive immune response to self-antigens and JAK-STAT signalling is known to play a key role in this process. Thus JAK inhibitors have considerable potential for the development of drugs to treat autoimmunity. JAK3 is an especially attractive target as, unlike other JAKs, its expression is restricted to the immune system. Several pharmaceutical companies have considerable efforts underway to develop JAK3 inhibitors. While the FDA recently approved the JAK3 inhibitor Tofacitnib (XELJANZ®), which is actually a pan-JAK inhibitor, it was rejected by CHMP in Europe due to safety concerns. This highlights the fact that while pan-JAK inhibitors are effective in RA, they carry a range of adverse side effects, many of which may relate to the functions of JAKs outside the adaptive immune system. Therefore, development of selective small molecule inhibitors of JAK3 would potentially represent a promising class of novel therapeutics.
Inducing protein degradation using hydrophobic tags is a strategy that has recently received attention from the scientific community. For example, Crews and co-workers discovered that covalent attachment of a hydrophobic tag to a dehalogenase fusion protein is effective in modulating the level of the transgenic fusion protein. See, e.g., Neklesa et al., Nature Chemical Biology (2011) 7:538-543. Hydrophobic tags used to induce protein degradation may eventually be found useful in a variety of applications, such as, for example, tagged therapeutic agents and tagged research tools for inducing protein degradatation in vivo and in vitro. However, the development of such hydrophobically tagged agents and tools is underrealized and continues to remain of great interest.